Editing Integrin (section)

== Function ==
Integrins have two main functions, attachment of the cells to the ECM and signal transduction from the ECM to the cells.<ref>{{cite journal | vauthors = Yamada KM, Miyamoto S | title = Integrin transmembrane signaling and cytoskeletal control | journal = Current Opinion in Cell Biology | volume = 7 | issue = 5 | pages = 681–9 | date = October 1995 | pmid = 8573343 | doi = 10.1016/0955-0674(95)80110-3 }}</ref> They are also involved in a wide range of other biological activities, including extravasation, cell-to-cell adhesion, cell migration, and as receptors for certain viruses, such as [[adenovirus]], [[echovirus]], [[hantavirus]], [[foot-and-mouth disease]], [[polio virus]] and other viruses. Recently, the importance of integrins in the progress of autoimmune disorders is also gaining attention of the scientists. These mechanoreceptors seem to regulate autoimmunity by dictating various intracellular pathways to control immune cell adhesion to endothelial cell layers followed by their trans-migration. This process might or might not be dependent on the sheer force faced by the extracellular parts of different integrins.<ref>{{cite journal |last1=Banerjee |first1=S |last2=Nara |first2=R |last3=Chakraborty |first3=S |last4=Chowdhury |first4=D |last5=Haldar |first5=S |title=Integrin Regulated Autoimmune Disorders: Understanding the Role of Mechanical Force in Autoimmunity. |journal=Frontiers in Cell and Developmental Biology |date=2022 |volume=10 |pages=852878 |doi=10.3389/fcell.2022.852878 |pmid=35372360 |pmc=8971850 |doi-access=free }}</ref>

A prominent function of the integrins is seen in the molecule [[Glycoprotein IIb/IIIa|GpIIb/IIIa]], an integrin on the surface of blood [[platelet]]s (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIb/IIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.

=== Attachment of cell to the ECM ===
Integrins couple the cell-[[extracellular matrix]] (ECM) outside a cell to the [[cytoskeleton]] (in particular, the [[microfilament]]s) inside the cell. Which ligand in the ECM the integrin can bind to is defined by which α and β subunits the integrin is made of. Among the [[ligand]]s of integrins are [[fibronectin]], [[vitronectin]], [[collagen]], and [[laminin]]. The connection between the cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in [[ontogeny]].

Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like [[Vascular endothelial growth factor|VEGF]], [[epidermal growth factor|EGF]], and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart of many cellular biological processes. The attachment of the cell takes place through formation of [[cell adhesion]] complexes, which consist of integrins and many cytoplasmic proteins, such as [[talin (protein)|talin]], [[vinculin]], [[paxillin]], and alpha-[[actinin]]. These act by regulating [[kinase]]s such as FAK ([[focal adhesion kinase]]) and [[Src kinase]] family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as [[CRK (gene)|CRK]]. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin α6β4 is an exception: it links to the keratin intermediate filament system in epithelial cells.<ref name="pmid16581764">{{cite journal | vauthors = Wilhelmsen K, Litjens SH, Sonnenberg A | title = Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis | journal = Molecular and Cellular Biology | volume = 26 | issue = 8 | pages = 2877–86 | date = April 2006 | pmid = 16581764 | pmc = 1446957 | doi = 10.1128/MCB.26.8.2877-2886.2006 }}</ref>

Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering.  The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signaling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy.<ref name="pmid20805876">{{cite journal | vauthors = Olberding JE, Thouless MD, [[Ellen Arruda|Arruda EM]], Garikipati K | title = The non-equilibrium thermodynamics and kinetics of focal adhesion dynamics | journal = PLOS ONE | volume = 5 | issue = 8 | pages = e12043 | date = August 2010 | pmid = 20805876 | pmc = 2923603 | doi = 10.1371/journal.pone.0012043 | veditors = Buehler MJ | bibcode = 2010PLoSO...512043O | doi-access = free }}</ref> As previously stated, these complexes  connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5&nbsp;nm and spaced at approximately 45&nbsp;nm.<ref name="pmid20694000">{{cite journal | vauthors = Patla I, Volberg T, Elad N, Hirschfeld-Warneken V, Grashoff C, Fässler R, Spatz JP, Geiger B, Medalia O | title = Dissecting the molecular architecture of integrin adhesion sites by cryo-electron tomography | journal = Nature Cell Biology | volume = 12 | issue = 9 | pages = 909–15 | date = September 2010 | pmid = 20694000 | doi = 10.1038/ncb2095 | s2cid = 20775305 }}</ref> Treatment with Rho-kinase inhibitor [[Y-27632]] reduces the size of the particle, and it is extremely mechanosensitive.<ref name="urlMechanosensitive channels">{{cite web| url =http://www.ks.uiuc.edu/Research/MscLchannel/| title =Mechanosensitive channels| vauthors =Gullingsrud J, Sotomayor M| publisher =Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology: University of Illinois at Urbana-Champaign| url-status =live| archive-url =https://web.archive.org/web/20101202060530/http://www.ks.uiuc.edu/Research/MscLchannel/| archive-date =2010-12-02}}</ref>

One important function of integrins on cells in tissue culture is their role in [[cell migration]]. Cells adhere to a [[substrate (biology)|substrate]] through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by [[endocytosis]]; they are transported through the cell to its front by the [[endocytic cycle]], where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front.<ref>{{cite journal | vauthors = Paul NR, Jacquemet G, Caswell PT | title = Endocytic Trafficking of Integrins in Cell Migration | language = en | journal = Current Biology | volume = 25 | issue = 22 | pages = R1092-105 | date = November 2015 | pmid = 26583903 | doi = 10.1016/j.cub.2015.09.049 | doi-access = free }}</ref> The cycle of integrin endocytosis and recycling back to the cell surface is important for migrating cells and also during animal development.<ref>{{cite journal | vauthors = Moreno-Layseca P, Icha J, Hamidi H, Ivaska J | title = Integrin trafficking in cells and tissues | journal = Nature Cell Biology | volume = 21 | issue = 2 | pages = 122–132 | date = February 2019 | pmid = 30602723 | pmc = 6597357 | doi = 10.1038/s41556-018-0223-z }}</ref>

=== Signal transduction ===
Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally  was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling. 
Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor.<ref>{{cite journal | vauthors = Goel HL, Breen M, Zhang J, Das I, Aznavoorian-Cheshire S, Greenberg NM, Elgavish A, Languino LR | title = beta1A integrin expression is required for type 1 insulin-like growth factor receptor mitogenic and transforming activities and localization to focal contacts | journal = Cancer Research | volume = 65 | issue = 15 | pages = 6692–700 | date = August 2005 | pmid = 16061650 | doi = 10.1158/0008-5472.CAN-04-4315 | doi-access =  }}</ref>  In a reverse direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor tyrosine kinases and their associated signaling molecules.

The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signaling pathways regulating cell behavior. Clustering and activation of the integrins/actin complexes strengthen the focal adhesion interaction and initiate the framework for cell signaling through assembly of adhesomes.<ref name="pmid21307119">{{cite journal | vauthors = Kim SH, Turnbull J, Guimond S | title = Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor | journal = The Journal of Endocrinology | volume = 209 | issue = 2 | pages = 139–51 | date = May 2011 | pmid = 21307119 | doi = 10.1530/JOE-10-0377 | doi-access =  }}</ref>

Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience:
* [[cell growth]]<ref name=":0">{{cite book | vauthors = Bostwick DG, Cheng L | chapter = 9 - Neoplasms of the Prostate|date=2020-01-01 | title = Urologic Surgical Pathology | edition = Fourth |pages=415–525.e42| veditors = Cheng L, MacLennan GT, Bostwick DG |place=Philadelphia|publisher=Content Repository Only!|language=en|isbn=978-0-323-54941-7 }}</ref>
* [[cell division]]<ref name=":0" />
* cell survival<ref name=":0" />
* [[cellular differentiation]]
* [[apoptosis|apoptosis (programmed cell death)]]

Knowledge of the relationship between integrins and receptor tyrosine kinase has laid a foundation for new approaches to cancer therapy. Specifically, targeting integrins associated with RTKs is an emerging approach for inhibiting angiogenesis.<ref>{{cite journal | vauthors = Carbonell WS, DeLay M, Jahangiri A, Park CC, Aghi MK | title = β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma | journal = Cancer Research | volume = 73 | issue = 10 | pages = 3145–54 | date = May 2013 | pmid = 23644530 | pmc = 4040366 | doi = 10.1158/0008-5472.CAN-13-0011 }}</ref>

[[File:Figure 1 - Nieuwenhuis et al 2018 - Integrins promote axonal regeneration after injury of the nervous system - Biological Reviews - doi 10.1111-brv.12398.jpg|thumb|Integrins are localised at the growth cone of regenerating neurons.<ref name="Nieuwenhuis2018a" />]]